Water soluble derivative of erythromycin

ABSTRACT

A new water soluble derivative of erythromycin, namely, erythromycin aspartate, is provided. The product is prepared by reacting erythromycin base with a substantially equimolar amount of aspartic acid or the ammonium salt of aspartic acid. The resulting erythomycin aspartate, which may be recovered as a white crystalline powder, is quite soluble in water and provides substantially neutral aqueous solutions which may be administered by the parenteral route, as well as by other modes of administration, for treatment of infections caused by grampositive bacteria.

United States Patent 1191 Fabrizio 1 Oct. 22, 1974 WATER SOLUBLE DERIVATIVE 0F 2.830.982 4/1958 Stuinbrook et al. 260/210 ERYTHROMYCIN 2.857.312 10/1958 Stephens 167/65 I 2.967.l29 l/l96l Chi 1 l67/65 [75] Inventor: G ra o Fabrizio, ta Maria 3.040.025 6/1962 Murphy 1. 200/210 Caputa Vetere. ltaly 3.276.950 10/1906 Cardinal 167/511 [73] Assignee: Pierrel S.p.A., Via Turati. Milan.

I l Primary Examiner-Henry A. French Filed Dec 8 1972 Attorney, Agent. or Firm-Bacon & Thomas 211 Appl. No.: 313,485 [57] ABSTRACT Related US. Application Data [62] Division of Ser. No. 2,685. Jan. 13, 1970.1 .11. No. A new water Soluble der'vat've eryihmmycm 3764595' namely, erythromycin aspartate, is provided. The product is prepared by reacting erythromycin base [30] Foreign Application Priority Data with a substantially equimolar amount of aspartic acid 15 969 Gr tBfl', O2437/69 or the ammonium salt of aspartic acid. The resultmg ea erythomycm aspartate, which may be recovered as a white crystalline powder, is quite soluble in water and aqueous [58] 424/181 may be administered by the parenteral route, as well 1e 0 earc as by other modes of administration, for treatment of l References Cited infections caused by gram-positive bacteria.

UNITED STATES PATENTS 2.761.859 9/1956 Hofihein 260/210 3 Claims, No Drawings This is a division, of application Ser. No. 2,685, filed Jan. 13, 1970, and issued as Pat. No. 3,764,595 issued Oct. 9, 1973.

it is known that erthromycin and certain erythromy cin derivatives in the form of salts or esters, are useful compounds for the treatment of diseases and infections caused by gram-positive bacteria both in veterinary and human medicine.

The administration of erythromycin or its derivatives can be made by various routes, as for instance orally, intramuscularly, intravenously and rectally. However, the route of administration which achieves the be therapeutic results is the parenteral one.

Erythromycin in the form of the free base has a very slight solubility in water (1 mg./ml.) and consequently its solutions have no therapeutical interest for the parenteral administration.

Among the various salts and esters of erythromycin already known and employed, there are some showing a very high solubility in water while still retaining a good antibiotic activity, and giving consequently solutions of therapeutically valuable concentrations.

However, the solubility of a certain antibiotic compound is not the only point which should be considered when evaluating its suitability and possible utilization for therapeutical purposes. The toxicity and tolerability, along with the antibiotic activity determined as the concentration in the blood during the time of treatment'(bl0od levels), are of the same and even greater order of importance.

As erthromycin has a basic nature, its conversion to salt form by reaction with an acid represents one of the best ways for obtaining a water soluble derivative. The choice of the salt-forming acid is of great importance as the chosen acid should be able to solubilize the erythromycin to a certain degree and must have a well determined acidity force in order to give a reduced acidity degree to the aqueous solutions of the erythromycin salts deriving therefrom.

It has been foundthat the products resulting from the acidification of erythromycin base with .dicarboxylicamino acids are very satisfactory. The dicarboxylicamino acids provide a buffering action in the aqueous solutions when one carboxylic group only is neutralized by erythromycin.

The preferred product is erythromycin aspartate which may be obtained by reacting erythromycin with l-aspartic acid or with a salt thereof. The erythromycin aspartate shows a very good solubility in water, more than 100 mg./ml. at a pH range 6.0 7.0 while retaining almost all the antibiotic activity.

The pH value of the aqueous solution of erythromycin aspartate is practically. neutral, thus maintaining a very good stability of the antibiotic substance which is known to be inactivated at acid pH values.

Another advantage of the product of the present in vention is that, the aqueous solutions of erythromycin aspartate being substantially neutral, the drug can be administered by the parenteral route. Moreover the compound may be included, without inconvenience, in the food and drinking water of animals.

The best way for preparing erythromycin aspartate is by the cross-reaction (double exchange-reaction) between erythromycin base and the ammonium salt of laspartic acid. The method has theadvantage of being exclusively carried out in a neutralor alkaline environment, maintaining consequently a good stability of the antibiotic substance.

Practically, the stoichiometric quantity of erythromycin base, which is previously dissolved in methanol, is added to an aqueous solution of ammonium laspartate. Ammonia is given off immediately and the pH value decreases to a constant value of about 7. The

aqueous solution may then be evaporated to dryness under vacuum at 50C maximum, A white crystalline powder is obtained, yvhich is soluble in water at a concentration of I00 iiigI/ml.

The erythromycin aspartate obtained by this method shows a purity degree which is quite satisfactory for therapeutic use and can also be employed as a feed supplement for animal use.

The preparation of the solid erythromycin aspartate from solution may be carried out by means of the commonly employed methods of liophylisation of the aqueous solution thereof, or by spray-drying the same solutions.

The aqueous solution of the water soluble erythromycin salt, which has a neutral pH, can also be satisfactorily employed in human therapy. However, when an erythromycin aspartate for human use is required, it is advisable to isolate the product by liophylisation. The product isolated by liophylisation presents the identical chemico-physical characteristics of the one obtained as before described.

The following examples are given by way of illustration of the invention only, without constituting'any limitationof the same:

EXAMPLE 1 14.68 gr. of erythromycin base and 2.66 gr. of laspartic acid are suspended in ml. of water. The solution is stirred for half an hour, then filtered and the reaction product is isolated from the solution by means of liophylisation. 17.3 gr. of the product with the following characteristics are obtained:

Aspect White, crystalline soluble in water 866.3

800-840 y/mg. as erythromycin base powder Molecular weight Microbiological activity Rotatory power 55 1 5 pH (10% solution) 6.0 7.0

Solubility in water Not less than 10% Contents of l-aspartic acid 13.5 I607:

EXAMPLE 2 The following details of pharmacological tests are given to illustrate the activity and effectiveness of DETERMINATION OF THE CONCENTRATION OF THE ANTIBIOTIC IN THE BLOOD different behavior has been evidenced between the two P du t eady ests? The new product maybe formulated in pharmaceutical composition form by use of a suitable vehicle'or The blood levels in the dog have been determined by carrier. Sterile m ectable liquids including water, saline injecting intramuscularly and intravenously 5 mg. of Solution and P may a Soluuon erythromycin aspartate activity, calculated as erythropendmg medum for Preparmg mlectflble Solutionsmycin base, per Kg of body weight, according to The product may also be compounded with sterile pow- Grove and v Randall ders, e.g., water-soluble excipients, etc. which act as a i th f ll i bl th reported average values are carrier for the active material for preparing solutions, expressed i y/mlof serum; 7 V suspensions or other desired preparations.

Intramuscular administration Erythromycin aspartate 5 mg. activitylkg. b.w. g

30 minutes I lhr 2hr 4hr 8hr 24hr Intravenous administration Erythromycin aspartate 5 mg. activitylKg. b.w.

30 minutes Ihr 2hr 3hr 8hr 24hr ACUTE TOXICITY The erythromycin aspartate is a product characterized by a very low toxicity; in fact the LD50 determined after intravenous administration in a mouse has resulted 332 mg. activity per Kg. b.w.

Such a value is highly competitive in correspondence with other soluble salts of erythromycin.

LOCAL TOLERABILITY The local tolerability of the erythromycin aspartate has been tested by oedema test provocated on the mouse paw by a sub-plantare injection of 0.1 ml. of water solution dosed at 50 mg. activity/ml. of erythromycin aspartate in comparison with erythromycin lacqh qnatqaf sfitl., 60f, ZQ'L m. admin strat cunq 25 What I claim is:

l. A pharmaceutical composition containing erythromycin aspartate in association with a suitable pharmaceutical vehicle.

2. A pharmaceutical composition as claimed in claim 1, in which the vehicle is a sterile injectable solution or suspension medium, or a sterile powder providing a 

1. A PHARMACEUTICAL COMPOSITION CONSISTING ERYTHROMYCIN ASPARATE IN ASSOCIATION WITH A SUITABLE PHARMACEUTICAL VEHICLE.
 2. A pharmaceutical composition as claimed in claim 1, in which the vehicle is a sterile injectable solution or suspension medium, or a sterile powder providing a carrier for preparing a solution or suspension.
 3. An aqueous solution for adding to animal drinking water containing erythromycin aspartate, prepared by dissolving in water a solid composition containing erythromycin aspartate with or without a water-soluble excipient. 